Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I.
Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I.
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DOI：
10.1172/jci23915
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发表时间：
2005-05
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影响因子：
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通讯作者：
Jenelle M. Timmins;Ji-Young Lee;Elena Y. Boudyguina;K. Kluckman;L. Brunham;A. Mulya;A. Gebre;Jonathan M C
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文献类型：
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作者：
Jenelle M. Timmins;Ji-Young Lee;Elena Y. Boudyguina;K. Kluckman;L. Brunham;A. Mulya;A. Gebre;Jonathan M C
丹吉尔病患者由于atp结合盒亚家族A成员1 （ABCA1）蛋白突变而表现出极低的血浆HDL浓度。ABCA1通过介导胆固醇和磷脂从细胞向无脂apoa - 1的外排来控制HDL颗粒组装的限速步骤，apoa - 1形成新生的HDL颗粒。ABCA1广泛表达；然而，参与HDL生物发生的具体组织尚不清楚。为了确定肝脏在HDL生物发生中的作用，我们只在肝脏中靶向缺失Abca1的第二个核苷酸结合结构域（Abca1(-L/-L)）的小鼠。Abca1（-L/-L）小鼠的总血浆和高密度脂蛋白胆固醇浓度分别为野生型鼠的19%和17%。野生型小鼠或人无脂apoA-I的体内分解代谢在Abca1（-L/-L）小鼠中比对照高2倍，这是由于肾脏对apoA-I的分解代谢增加了2倍，而肝脏的分解代谢没有变化。我们的结论是，在喂食小鼠中，肝脏是血浆高密度脂蛋白最重要的来源。此外，在肝脏（而非肝外），Abca1对维持成熟HDL颗粒的循环至关重要，通过直接脂化肝脏贫脂apoa - 1，减缓其通过肾脏的分解代谢并延长其在血浆中的停留时间。
Patients with Tangier disease exhibit extremely low plasma HDL concentrations resulting from mutations in the ATP-binding cassette, sub-family A, member 1 (ABCA1) protein. ABCA1 controls the rate-limiting step in HDL particle assembly by mediating efflux of cholesterol and phospholipid from cells to lipid-free apoA-I, which forms nascent HDL particles. ABCA1 is widely expressed; however, the specific tissues involved in HDL biogenesis are unknown. To determine the role of the liver in HDL biogenesis, we generated mice with targeted deletion of the second nucleotide-binding domain of Abca1 in liver only (Abca1(-L/-L)). Abca1(-L/-L) mice had total plasma and HDL cholesterol concentrations that were 19% and 17% those of wild-type littermates, respectively. In vivo catabolism of HDL apoA-I from wild-type mice or human lipid-free apoA-I was 2-fold higher in Abca1(-L/-L) mice compared with controls due to a 2-fold increase in the catabolism of apoA-I by the kidney, with no change in liver catabolism. We conclude that in chow-fed mice, the liver is the single most important source of plasma HDL. Furthermore, hepatic, but not extrahepatic, Abca1 is critical in maintaining the circulation of mature HDL particles by direct lipidation of hepatic lipid-poor apoA-I, slowing its catabolism by the kidney and prolonging its plasma residence time.